Difluoro ketone peptidomimetics suggest a large s1 pocket for Alzheimer’s γ-secretase: implications for inhibitor design was written by Moore, Chad L.;Leatherwood, Dartha D.;Diehl, Thekla S.;Selkoe, Dennis J.;Wolfe, Michael S.. And the article was included in Journal of Medicinal Chemistry in 2000.Reference of 87694-53-9 This article mentions the following:
The final step in the generation of the amyloid-β protein (Aβ), implicated in the etiol. of Alzheimer’s disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by γ-secretase. Although considered an important target for therapeutic design, γ-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alc. transition-state analog inhibitors suggest that γ-secretase is an aspartyl protease with loose sequence specificity. To further characterize the active site of γ-secretase, we prepared a series of difluoro ketone peptide analogs with varying steric bulkiness in the P1 position and tested the ability of these compounds to inhibit Aβ production in APP-transfected cells. Incorporation of bulky, aliphatic P1 side chains, such as sec-Bu or cyclohexylmethyl, led to increased γ-secretase inhibitory potency, suggesting a large S1 pocket to accommodate these substituents and providing further evidence for loose sequence specificity. The cyclohexylmethyl P1 substituent allowed N-terminal truncation to a low-mol.-weight compound (<600 Da) that effectively blocked Aβ production (IC50 â?5 μM). This finding suggests that optimal S1 binding may allow the development of potent inhibitors with ideal pharmaceutical properties. Moreover, a difluoro alc. analog with a cyclohexylmethyl P1 substituent was equipotent with its difluoro ketone counterpart, providing strong evidence that γ-secretase is an aspartyl protease. All new analogs inhibited total Aβ and Aβ42 production with the same rank order of potency and increased Aβ42 production at low concentrations, providing further evidence for distinct γ-secretases that are nevertheless closely similar with respect to active site topol. and mechanism. In the experiment, the researchers used many compounds, for example, (S)-tert-Butyl (1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (cas: 87694-53-9Reference of 87694-53-9).
(S)-tert-Butyl (1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (cas: 87694-53-9) belongs to esters. Volatile esters with characteristic odours are used in synthetic flavours, perfumes, and cosmetics. Certain volatile esters are used as solvents for lacquers, paints, and varnishes. Liquid esters of low volatility serve as softening agents for resins and plastics. Esters also include many industrially important polymers. Polymethyl methacrylate is a glass substitute sold under the names Lucite and Plexiglas; polyethylene terephthalate is used as a film (Mylar) and as textile fibres sold as Terylene, Fortrel, and Dacron.Reference of 87694-53-9
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